- Email: [email protected]
Phase II Trial of Intravesical Nanoparticle Albumin Bound Paclitaxel for the Treatment of Nonmuscle Invasive Urothelial Carcinoma of the Bladder after bacillus Calmette-Guérin Treatment Failure
Phase II Trial of Intravesical Nanoparticle Albumin Bound Paclitaxel for the Treatment of Nonmuscle Invasive Urothelial rin Carcinoma of the Bladder after bacillus Calmette-Gue Treatment Failure James M. McKiernan,* Dara D. Holder, Rashed A. Ghandour, LaMont J. Barlow, Jennifer J. Ahn,† Max Kates, Gina M. Badalato, Arindam Roychoudhury,‡ G. Joel Decastro and Mitchell C. Benson From the Department of Urology, Herbert Irving Cancer Center (JMM, DDH, RAG, LJB, JJA, MK, GMB, GJD, MCB) and Department of Biostatistics, Mailman School of Public Health (AR), Columbia University Medical Center, New York, New York
Purpose: Response rates to current second line intravesical therapies for recurrent nonmuscle invasive bladder cancer range between 10% and 30%. Nanoparticle albumin bound (nab-)paclitaxel has increased solubility and lower toxicity compared to other taxanes. Results of the phase I intravesical trial of this compound demonstrated minimal toxicity during dose escalation. We now report the results of a phase II trial to assess efficacy. Materials and Methods: This study was an investigator initiated, single center, single arm, phase II trial investigating the use of nab-paclitaxel in patients with recurrent Tis, T1 and Ta urothelial carcinoma in whom at least 1 prior regimen of intravesical bacillus Calmette-Gu erin failed. Patients received 500 mg/100 ml nab-paclitaxel administered in 6 weekly intravesical instillations. Efficacy was evaluated with cystoscopy, biopsy, cytology and imaging. If complete response was achieved, patients were treated with full dose monthly maintenance treatments for 6 months. Results: A total of 28 patients were enrolled in the study. Of these patients 10 (35.7%) exhibited a complete response after initial treatment. At 1 year all of these responses remained durable after maintenance therapy. At a mean followup of 21 months (range 5 to 47) 19 of 28 (67.8%) patients retained their bladders without progression or distant metastases. A single patient had progression to muscle invasive disease at radical cystectomy. Treatment related adverse events were noted in 9 of 28 (32.1%) patients and were limited to grade 1 or 2. Conclusions: Intravesical nab-paclitaxel has minimal toxicity and a 35.7% response rate in patients with nonmuscle invasive bladder cancer and previous bacillus Calmette-Gu erin failure. Complete response remained durable at 1 year followup in this heavily pretreated patient population. Key Words: urinary bladder neoplasms; intravesical administration; therapies, investigational; paclitaxel; nanotechnology
IN 2013 the incidence of bladder cancer in the United States was 72,500 with approximately 15,000 deaths.1
Abbreviations and Acronyms BCG ¼ bacillus Calmette-Guerin CFS ¼ cystectomy-free survival CIS ¼ carcinoma in situ CR ¼ complete response MDD ¼ maximal deliverable dose nab ¼ nanoparticle albumin bound NMIBC ¼ nonmuscle invasive bladder cancer RC ¼ radical cystectomy RFS ¼ recurrence-free survival Accepted for publication June 25, 2014. Study received institutional review board approval. Supported by an investigator initiated grant from Celgene Pharmaceutical. No edits to the manuscript were performed by the Celgene editorial office. * Correspondence: Department of Urology, Columbia University Medical Center, 161 Fort Washington Ave., Herbert Irving Pavilion, 11th Floor, New York, New York 10032 (telephone: 212305-5526; FAX: 212-305-6813; e-mail: jmm23@ columbia.edu). † Financial interest and/or other relationship with Celgene. ‡ Financial interest and/or other relationship with Novartis.
Urothelial carcinoma constitutes more than 90% of cases and approximately 70% present initially with NMIBC.2
0022-5347/14/1926-1633/0 THE JOURNAL OF UROLOGY® © 2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
http://dx.doi.org/10.1016/j.juro.2014.06.084 Vol. 192, 1633-1638, December 2014 Printed in U.S.A.
www.jurology.com
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In 1976 Morales reported the therapeutic efficacy of BCG in high grade NMIBC.3 Subsequently BCG has become the gold standard treatment. Currently the American Urological Association and European Association of Urology recommend intravesical BCG as first line treatment after transurethral resection of high grade NMIBC.4,5 Fiveyear recurrence rates after BCG induction with maintenance range from 30% to 60% depending on stage, grade, multiplicity and length of followup.3,6,7 Recurrent NMIBC is a heterogeneous disease state, and can be defined and characterized using terms such as refractory, resistant and relapsing. With a progression risk of 20% to 30% in this setting, radical cystectomy is currently the standard of care.4e8 Second line novel agents have been an area of active investigation. To date, valrubicin is the only FDA (Food and Drug Administration) approved intravesical therapy for BCG refractory NMIBC and has been associated with an 18% to 21% CR rate in studies limited exclusively to patients with CIS.9,10 Multiple other agents have been investigated, including BCG combined with alpha-interferon, mitomycin C with or without electromotive and hyperthermic techniques, gemcitabine, docetaxel and combination intravesical chemotherapy in preclinical studies.11e13 In 2006 we reported the results of 18 patients in a phase I clinical trial of intravesical docetaxel for the treatment of recurrent NMIBC after BCG therapy.14 Docetaxel showed no systemic absorption and minimal toxicity, and a 56% CR at initial assessment in that trial, with a 4-year recurrence-free survival of 22%. In that phase I trial the maximal tolerated dose and safety profile were the primary end points.12,15 Paclitaxel, another taxane and microtubule depolymerization inhibitor, is used for systemic treatment of multiple cancers and, in its nanoparticle albumin bound (nab-) form, is currently an FDA approved systemic therapy for breast and pancreatic cancer.16,17 Nab-paclitaxel has a fivefold higher solubility in aqueous environments compared to docetaxel and a facilitated drug delivery mechanism into tumor cells via albumin receptor mediated transport across epithelial cells.17,18 A third mechanism of improved action is through the newly described SPARC tumor interstitium protein, which mediates transcytosis into tumor cells.19 The first human phase I trial of intravesical nab-paclitaxel was published in 2011, with an encouraging safety profile and acceptable secondary end points of efficacy.20 The current phase II study used the MDD of nab-paclitaxel to further explore the activity of this agent in the treatment of high risk NMIBC that has relapsed or persisted after BCG therapy.
MATERIALS AND METHODS Study Design This study was a single center, prospective, institutional review board approved (IRB-AAAC1114), investigator initiated and industry sponsored phase II nonrandomized trial. The MDD was 500 mg in 100 ml normal saline in the previously published phase I study.20 A Simon 2-stage design was used. There were 10 patients enrolled in the first stage, and only when 2 or more of those patients responded, 18 additional patients were evaluated in the second stage. The probability of correctly concluding the therapy is worthy of further study was calculated to be 80% if the true underlying response rate was 30%. The probability of incorrectly concluding the therapy is promising was 5% if the true response rate was approximately 10%.21e23 The expected sample size for this study design was a minimum of 15 and a maximum of 28 patients.
Patient Eligibility Patients eligible for this study all had high risk NMIBC with pathologically proven stage T1, Ta or Tis. Patients had high grade disease except 1 who had multifocal recurrent low grade stage Ta disease. All patients were subject to a minimum of 1 prior intravesical BCG induction course. Prior use of intravesical mitomycin C, interferon, gemcitabine, docetaxel or other experimental clinical agents was allowed. If a patient was treated in a prior clinical trial, a minimum of 3 months after completion of the prior protocol was required with documented disease recurrence before enrollment in this study. All patients had grossly visible disease fully resected with pathological confirmation of histology before enrollment. They were offered RC as the gold standard option and refused, or were at unacceptable surgical risk. Patients underwent pretreatment assessment including physical examination, cystoscopy and cross-sectional imaging, as well as complete blood count, basic metabolic panel, hepatic function panel and coagulation profile before study enrollment. Additional inclusion criteria were age 18 years or older, ability to provide informed consent, Eastern Cooperative Oncology Group performance status 0 or 1, mild or no peripheral neuropathy, no hematological disturbances as defined by neutrophil count 1,500/mm3 or less, hemoglobin 9 gm/dl or less, or platelet count 100,000/mm3 or less, no hepatic dysfunction as defined by abnormal bilirubin or liver function tests 2.5 or greater than upper normal limit, no renal dysfunction as defined by serum creatinine 2.0 mg/dl or greater, negative pregnancy test in women of childbearing age and no intravesical therapy within 6 weeks before enrollment. Exclusion criteria were prior systemic taxane therapy, any other malignancy diagnosed within 2 years of study entry (except nonmelanoma skin cancer, chronic lymphocytic leukemia or noninvasive cervical cancer), concurrent treatment with any chemotherapeutic agent, pregnant or lactating women, history of vesicoureteral reflux or an indwelling urinary stent, or administration of any investigational agent within 3 months before study.
Drug Preparation and Administration The dose of nab-paclitaxel was the MDD of 500 mg/100 ml 0.9% NaCl. The dose was instilled intravesically on a
NAB-PACLITAXEL FOR BACILLUS CALMETTE-GUERIN REFRACTORY BLADDER CANCER
weekly basis for 6 weeks as induction and on a monthly basis for 6 months as maintenance in case of response. On the day of each instillation an updated history and physical examination were performed, and a urine pH was measured by dipstick to be in the range of 5 to 7.5 to ensure nab-paclitaxel solubility. Sterile urethral catheterization was performed to empty the bladder and instill nab-paclitaxel solution into the bladder with a drug retention time of 2 hours.
Treatment Assessment and Evaluation After induction treatment, initial response was assessed through urine cytology, cystoscopy with biopsy, directed and random, 6 weeks after the last instillation of the induction nab-paclitaxel course. Cross-sectional imaging was included in the posttreatment evaluation. CR was defined by the absence of any residual carcinoma in the biopsy specimen as well as in cytology following the combination of maximal transurethral resection and nab-paclitaxel. The efficacy of this protocol was measured using the CR rate as the primary end point, and recurrence-free and cystectomy-free survival as the secondary end points. Local toxicity symptoms were monitored throughout treatment, and graded using the Common Terminology Criteria for Adverse Events, version 3.0, published by the National Cancer Institute. Treatment was delayed by 1 week if grade 2 local toxicity developed, then resumed if symptoms improved. Grade 3 or 4 toxicity prompted discontinuation of therapy.
RESULTS A total of 28 patients were enrolled in the study between 2010 and 2013. Median patient age was 76 years (range 33 to 91), and 22 men and 6 women were enrolled. All patients had nonmuscle invasive urothelial carcinoma of the bladder, with disease stage and grade presented in table 1. Only 1 patient had unifocal T1 while all the remaining had multifocal disease. The median number of prior courses of intravesical therapy was 2, with 7 patients who received 1 course and 9 who received 3 or more courses, including enrollment in prior clinical trials of intravesical chemotherapy. Of the 28 patients 6 (21.4%) previously received intravesical
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chemotherapy (mitomycin C or other agents) subsequent to BCG with or without interferon (table 2). Only 1 patient previously responded to BCG then experienced relapse, yet he never received maintenance. No other patient in this study previously received BCG maintenance. Twenty patients refused and 8 were medically unfit for cystectomy. Median followup was 21 months (range 5 to 47). Twenty-six patients completed the 6 intravesical induction instillations and the remaining 2 patients were still included in the analysis of efficacy. On initial posttreatment assessment 6 weeks after the last induction instillation, 10 of the 28 patients (35.7%) had a CR. The pretreatment stages stratified by response status and the posttreatment stages and cytology are presented in table 3. Among the 10 responders 8 received the entire induction course followed by 6 months of maintenance therapy. The 2 who did not complete induction also did not receive maintenance therapy. Of the 10 responders 2 elected to continue on maintenance therapy off protocol following the conclusion of the 6-month maintenance period. One of these patients exhibited positive cytology 14 months after enrollment with normal cystoscopic examination until 45 months of followup, and refused further biopsy. Two patients died of unrelated causes at 11 and 24 months of followup. The remaining 7 patients were disease-free at a median followup of 21 months. All 18 nonresponders were recommended by the urologist to proceed to RC yet only 9 accepted and followed the recommendation. Of these 9 patients 7 are alive with no evidence of local or systemic disease. One died 9 weeks after RC due to perioperative complications with final pathology showing CIS only. A single patient undergoing RC exhibited stage progression to muscle invasive disease (pT2N0M0) on surgical pathology, and eventually died of metastatic urothelial cancer 18 months after treatment initiation. Of the 18 patients who did not respond to nabpaclitaxel therapy 9 did not undergo cystectomy. Table 2. Intravesical treatment history of participants
Table 1. Demographic and clinical characteristics of participants
No. (%) No. (%)
Gender: F M Clinical stage: Ta Ta þ Tis T1 T1 þ Tis Tis only Tumor grade: Low grade/multifocal Ta High grade
6 (21) 22 (79) 4 2 4 5 13
(14) (7) (14) (18) (46)
1 (4) 27 (96)
BCG alone induction BCG alone reinduction BCG maintenance BCG þ interferon Intravesical chemotherapy: Mitomycin Gemcitabine Mitomycinþgemcitabine Valrubicin No. cycles: 1 2 3 4
27 6 0 13 6 1 3 1 1
(96) (21) (46) (21) (3.6) (11) (3.6) (3.6)
7 12 8 1
(25) (43) (29) (3.6)
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Table 3. Assessment of patients before and after treatment No. Complete Responders (%)
No. Noncomplete Responders (%)
Before nab-paclitaxel treatment* Stage: Ta Ta þ Tis T1 T1 þ Tis Tis only Stage on biopsy: T0 Ta (þTis) T1 (þTis) Tis Cytology: Malignant Suspicious Benign
3 (30) 0 (0) 2 (20) 1 (10) 4 (40) After nab-paclitaxel treatment
1 2 2 4 9
(5.6) (11) (11) (22) (50)
10 0 (0) 0 (0) 0
0 2 (2) 2 (3) 9
0 (0) 4 (40) 6 (60)
11 (61) 3 (17) 4 (22)
* p<0.001.
Two died of unrelated causes, both within 12 months of initiation of treatment. The remaining 7 patients all had residual high grade NMIBC, 4 have not received further intravesical therapy and 3 went on to receive further intravesical therapy (2 docetaxel and 1 valrubicin), with 1 completely responding to docetaxel and 1 completely responding to valrubicin. None of those 9 exhibited stage progression at a median followup of 21 months. In this study 19 of 28 patients retained their bladders without disease progression or metastasis. RFS was 35.7% at 1 year and 30.6% at 2 years of followup. CFS at 12, 24 and 36 months was 74%, 74% and 55%, respectively. RFS and CFS are presented in Kaplan-Meier survival analysis plots (see figure). Nine patients (32%) experienced adverse events in this study. All events were grade 1 or 2, and included fatigue, urinary urgency and self-limiting hematuria for grade 1 (4 of 28 patients, 14%). Grade 2 toxicities (5 of 28 patients, 18%) included urinary tract infection, frequency and urgency, and gross hematuria. No patient underwent
discontinuation of therapy because of a drug related event. One patient received only 3 of the planned 6 instillations due to unrelated pneumonia, while another patient withdrew from the trial due to recurrent urinary tract infections after receiving only 2 instillations. These infections were multidrug resistant, present for more than 2 years before enrollment and due to incomplete bladder emptying. No grade 3 or higher toxicity was noted.
DISCUSSION High risk NMIBC represents a challenging disease state to manage. While intravesical BCG is a well established first line treatment for patients with NMIBC, patients with recurrence after the initial treatment have lower response rates to subsequent courses.24 BCG was previously compared as an induction agent to adjuvant intravesical chemotherapy. However, it was only compared to mitomycin, epirubicin and doxorubicin.8,25 Alternative agents that have proven successful in the systemic therapy of advanced urothelial carcinoma such as cisplatin, gemcitabine and docetaxel have now been investigated intravesically with varying yet promising results. Intravesical gemcitabine in particular was supported by multiple studies in patients with high risk disease. In a study by Gunelli et al a group of 40 patients without CIS had a CR rate of 95% at 6 months and disease-free survival of 66% at 24 months.26 However, a separate study by Dalbagni et al of 30 patients (which included 23 patients with CIS) showed a 20% disease-free survival at 12 months without the use of maintenance therapy for responders.27 The most recent trial of gemcitabine was conducted by Skinner et al of the Southwest Oncology Group and was reported in 2013.11 They found a 47% complete initial response rate at 3 months and a RFS of 28% and 21% at 1 and 2 years, respectively. Of note, maintenance
Disease-free (A) and cystectomy-free (B) survival after intravesical nab-paclitaxel
NAB-PACLITAXEL FOR BACILLUS CALMETTE-GUERIN REFRACTORY BLADDER CANCER
intravesical gemcitabine was given to complete responders. Intravesical taxane therapy has been a topic of interest at our institution since initiating our initial phase I trial of intravesical docetaxel in 2003. The results of this trial were published in 2006, and demonstrated acceptable safety and efficacy profiles.14 However, no phase II trial of efficacy was conducted.15 Paclitaxel, another taxane, recently became available in an albumin bound formulation, improving its pharmacokinetics and safety profile, and theoretically its efficacy in targeting cancerous cells. In our prospective phase II trial of efficacy in a heavily pretreated high risk population of patients with NMIBC, a CR rate of 35.7% was achieved. More importantly, all patients who responded remained disease-free at 1 year, and RFS at 2 years and at last followup was 30.6%, with a median followup of 21 months. These results demonstrate a durability of response to intravesical nab-paclitaxel induction plus maintenance not seen in any previous taxane based clinical trial. All patients were compliant with the induction and maintenance therapy schedules and specified followup except for 2 patients as described earlier. However, these 2 patients were included in the final analysis of therapy outcomes. Since this was a single arm study in which all complete initial responders were offered monthly maintenance therapy throughout the duration of recurrence-free status for up to 6 additional treatments, the effect of maintenance therapy on durability could not be assessed. With a favorable safety profile, minimal absorption and a 6,000-fold greater bladder tissue concentration for intravesical therapy over systemic therapy,28 maintenance seems to be justified and practical. It is even possible that the durability seen in the current study could be improved with
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additional maintenance treatments beyond those allowed by our protocol. Prospective, randomized studies are required to determine the ideal treatment schedule and the true effect of maintenance intravesical nab-paclitaxel. Although CFS is not a widely studied or a widely accepted outcome in bladder cancer literature, it provides a method to describe the likelihood of bladder preservation in this population facing RC as the standard of care, particularly in studies of similar design and objective. The relatively short followup and limited sample size of this phase II trial limit any broad conclusions regarding the future role of nab-paclitaxel in patients with recurrent high risk NMIBC after BCG. To resolve the role of novel agents in this setting, a definitive randomized phase III trial comparing a novel therapeutic agent with BCG or a similar standard intervention will be required.
CONCLUSIONS This phase II study of intravesical nab-paclitaxel demonstrated significant activity in high risk patients with recurrent NMIBC after treatment with BCG with or without other chemotherapeutic agents. In a heavily pretreated population the limited toxicity profile in conjunction with a CR of 35.7% warrants further investigation. Furthermore, the addition of maintenance therapy resulted in a durability of response not frequently seen in such populations. Either alone or in combination with other agents, nab-paclitaxel is a viable candidate for further study in this high risk population.
ACKNOWLEDGMENTS Jiibril Palmer and Matthew Danzig provided assistance.
REFERENCES 1. National Cancer Institute: SEER Stat Fact Sheets: Bladder Cancer, Statistics at a Glance, November 2013. Available at http://seer.cancer. gov/statfacts/html/urinb.html.
5. Babjuk M, Burger M, Zigeuner R et al: EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2013. Eur Urol 2013; 64: 639.
2. Jones JS: Non-muscle-invasive bladder cancer (Ta, T1, and CIS). In: Campbell-Walsh Urology, 10th ed. Edited by L Kavoussi, A Partin, A Novick et al. Philadelphia: Saunders 2012; vol 3, p 2335.
6. Lamm DL, Blumenstein BA, Crissman JD et al: Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol 2000; 163: 1124.
3. Morales A: Long-term results and complications of intracavitary bacillus Calmette-Guerin therapy for bladder cancer. J Urol 1984; 132: 457. 4. Hall MC, Chang SS, Dalbagni G et al: Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update. J Urol 2007; 178: 2314.
7. Herr HW, Wartinger DD, Fair WR et al: Bacillus Calmette-Guerin therapy for superficial bladder cancer: a 10-year followup. J Urol 1992; 147: 1020. 8. Gontero P, Bohle A, Malmstrom PU et al: The role of bacillus Calmette-Guerin in the treatment
of non-muscle-invasive bladder cancer. Eur Urol 2010; 57: 410. 9. Dinney CP, Greenberg RE and Steinberg GD: Intravesical valrubicin in patients with bladder carcinoma in situ and contraindication to or failure after bacillus Calmette-Guerin. Urol Oncol 2013; 31: 1635. 10. Steinberg G, Bahnson R, Brosman S et al: Efficacy and safety of valrubicin for the treatment of bacillus Calmette-Guerin refractory carcinoma in situ of the bladder. J Urol 2000; 163: 761. 11. Skinner EC, Goldman B, Sakr WA et al: SWOG S0353: phase II trial of intravesical gemcitabine in patients with nonmuscle invasive bladder cancer and recurrence after 2 prior courses of
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intravesical bacillus Calmette-Guerin. J Urol 2013; 190: 1200. 12. Laudano MA, Barlow LJ, Murphy AM et al: Long-term clinical outcomes of a phase I trial of intravesical docetaxel in the management of non-muscle-invasive bladder cancer refractory to standard intravesical therapy. Urology 2010; 75: 134. 13. Delto JC, Kobayashi T, Benson M et al: Preclinical analyses of intravesical chemotherapy for prevention of bladder cancer progression. Oncotarget 2013; 4: 269. 14. McKiernan JM, Masson P, Murphy AM et al: Phase I trial of intravesical docetaxel in the management of superficial bladder cancer refractory to standard intravesical therapy. J Clin Oncol 2006; 24: 3075. 15. Barlow L, McKiernan JM and Benson MC: Long-term survival outcomes with intravesical docetaxel for recurrent nonmuscle invasive bladder cancer after previous bacillus CalmetteGuerin therapy. J Urol 2013; 189: 834. 16. Saif MW: U.S. Food and Drug Administration approves paclitaxel protein-bound particles (AbraxaneÒ) in combination with gemcitabine as first-line treatment of patients with metastatic pancreatic cancer. JOP 2013; 14: 686.
17. Gradishar WJ, Tjulandin S, Davidson N et al: Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol 2005; 23: 7794. 18. Sparreboom A, Scripture CD, Trieu V et al: Comparative preclinical and clinical pharmacokinetics of a cremophor-free, nanoparticle albumin-bound paclitaxel (ABI-007) and paclitaxel formulated in Cremophor (Taxol). Clin Cancer Res 2005; 11: 4136. 19. Elsadek B and Kratz F: Impact of albumin on drug deliveryenew applications on the horizon. J Control Release 2012; 157: 4. 20. McKiernan JM, Barlow LJ, Laudano MA et al: A phase I trial of intravesical nanoparticle albuminbound paclitaxel in the treatment of bacillus Calmette-Guerin refractory nonmuscle invasive bladder cancer. J Urol 2011; 186: 448.
23. Herr HW: Transurethral resection and intravesical therapy of superficial bladder tumors. Urol Clin North Am 1991; 18: 525. 24. Catalona WJ, Hudson MA, Gillen DP et al: Risks and benefits of repeated courses of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. J Urol 1987; 137: 220. 25. Sylvester RJ, Oosterlinck W and Van der Meijden AP: A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: a meta-analysis of published results of randomized clinical trials. J Urol 2004; 171: 2186. 26. Gunelli R, Bercovich E, Nanni O et al: Activity of endovesical gemcitabine in BCG-refractory bladder cancer patients: a translational study. Br J Cancer 2007; 97: 1499.
21. Bartoletti R, Cai T, Gacci M et al: Intravesical gemcitabine therapy for superficial transitional cell carcinoma: results of a phase II prospective multicenter study. Urology 2005; 66: 726.
27. Dalbagni G, Russo P, Bochner B et al: Phase II trial of intravesical gemcitabine in bacille Calmette-Guerin-refractory transitional cell carcinoma of the bladder. J Clin Oncol 2006; 24: 2729.
22. Melekos MD and Moutzouris GD: Intravesical therapy of superficial bladder cancer. Curr Pharm Des 2000; 6: 345.
28. Song D, Wientjes MG and Au JL: Bladder tissue pharmacokinetics of intravesical taxol. Cancer Chemother Pharmacol 1997; 40: 285.
Purpose: Response rates to current second line intravesical therapies for recurrent nonmuscle invasive bladder cancer range between 10% and 30%. Nanoparticle albumin bound (nab-)paclitaxel has increased solubility and lower toxicity compared to other taxanes. Results of the phase I intravesical trial of this compound demonstrated minimal toxicity during dose escalation. We now report the results of a phase II trial to assess efficacy. Materials and Methods: This study was an investigator initiated, single center, single arm, phase II trial investigating the use of nab-paclitaxel in patients with recurrent Tis, T1 and Ta urothelial carcinoma in whom at least 1 prior regimen of intravesical bacillus Calmette-Gu erin failed. Patients received 500 mg/100 ml nab-paclitaxel administered in 6 weekly intravesical instillations. Efficacy was evaluated with cystoscopy, biopsy, cytology and imaging. If complete response was achieved, patients were treated with full dose monthly maintenance treatments for 6 months. Results: A total of 28 patients were enrolled in the study. Of these patients 10 (35.7%) exhibited a complete response after initial treatment. At 1 year all of these responses remained durable after maintenance therapy. At a mean followup of 21 months (range 5 to 47) 19 of 28 (67.8%) patients retained their bladders without progression or distant metastases. A single patient had progression to muscle invasive disease at radical cystectomy. Treatment related adverse events were noted in 9 of 28 (32.1%) patients and were limited to grade 1 or 2. Conclusions: Intravesical nab-paclitaxel has minimal toxicity and a 35.7% response rate in patients with nonmuscle invasive bladder cancer and previous bacillus Calmette-Gu erin failure. Complete response remained durable at 1 year followup in this heavily pretreated patient population. Key Words: urinary bladder neoplasms; intravesical administration; therapies, investigational; paclitaxel; nanotechnology
IN 2013 the incidence of bladder cancer in the United States was 72,500 with approximately 15,000 deaths.1
Abbreviations and Acronyms BCG ¼ bacillus Calmette-Guerin CFS ¼ cystectomy-free survival CIS ¼ carcinoma in situ CR ¼ complete response MDD ¼ maximal deliverable dose nab ¼ nanoparticle albumin bound NMIBC ¼ nonmuscle invasive bladder cancer RC ¼ radical cystectomy RFS ¼ recurrence-free survival Accepted for publication June 25, 2014. Study received institutional review board approval. Supported by an investigator initiated grant from Celgene Pharmaceutical. No edits to the manuscript were performed by the Celgene editorial office. * Correspondence: Department of Urology, Columbia University Medical Center, 161 Fort Washington Ave., Herbert Irving Pavilion, 11th Floor, New York, New York 10032 (telephone: 212305-5526; FAX: 212-305-6813; e-mail: jmm23@ columbia.edu). † Financial interest and/or other relationship with Celgene. ‡ Financial interest and/or other relationship with Novartis.
Urothelial carcinoma constitutes more than 90% of cases and approximately 70% present initially with NMIBC.2
0022-5347/14/1926-1633/0 THE JOURNAL OF UROLOGY® © 2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
http://dx.doi.org/10.1016/j.juro.2014.06.084 Vol. 192, 1633-1638, December 2014 Printed in U.S.A.
www.jurology.com
j
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In 1976 Morales reported the therapeutic efficacy of BCG in high grade NMIBC.3 Subsequently BCG has become the gold standard treatment. Currently the American Urological Association and European Association of Urology recommend intravesical BCG as first line treatment after transurethral resection of high grade NMIBC.4,5 Fiveyear recurrence rates after BCG induction with maintenance range from 30% to 60% depending on stage, grade, multiplicity and length of followup.3,6,7 Recurrent NMIBC is a heterogeneous disease state, and can be defined and characterized using terms such as refractory, resistant and relapsing. With a progression risk of 20% to 30% in this setting, radical cystectomy is currently the standard of care.4e8 Second line novel agents have been an area of active investigation. To date, valrubicin is the only FDA (Food and Drug Administration) approved intravesical therapy for BCG refractory NMIBC and has been associated with an 18% to 21% CR rate in studies limited exclusively to patients with CIS.9,10 Multiple other agents have been investigated, including BCG combined with alpha-interferon, mitomycin C with or without electromotive and hyperthermic techniques, gemcitabine, docetaxel and combination intravesical chemotherapy in preclinical studies.11e13 In 2006 we reported the results of 18 patients in a phase I clinical trial of intravesical docetaxel for the treatment of recurrent NMIBC after BCG therapy.14 Docetaxel showed no systemic absorption and minimal toxicity, and a 56% CR at initial assessment in that trial, with a 4-year recurrence-free survival of 22%. In that phase I trial the maximal tolerated dose and safety profile were the primary end points.12,15 Paclitaxel, another taxane and microtubule depolymerization inhibitor, is used for systemic treatment of multiple cancers and, in its nanoparticle albumin bound (nab-) form, is currently an FDA approved systemic therapy for breast and pancreatic cancer.16,17 Nab-paclitaxel has a fivefold higher solubility in aqueous environments compared to docetaxel and a facilitated drug delivery mechanism into tumor cells via albumin receptor mediated transport across epithelial cells.17,18 A third mechanism of improved action is through the newly described SPARC tumor interstitium protein, which mediates transcytosis into tumor cells.19 The first human phase I trial of intravesical nab-paclitaxel was published in 2011, with an encouraging safety profile and acceptable secondary end points of efficacy.20 The current phase II study used the MDD of nab-paclitaxel to further explore the activity of this agent in the treatment of high risk NMIBC that has relapsed or persisted after BCG therapy.
MATERIALS AND METHODS Study Design This study was a single center, prospective, institutional review board approved (IRB-AAAC1114), investigator initiated and industry sponsored phase II nonrandomized trial. The MDD was 500 mg in 100 ml normal saline in the previously published phase I study.20 A Simon 2-stage design was used. There were 10 patients enrolled in the first stage, and only when 2 or more of those patients responded, 18 additional patients were evaluated in the second stage. The probability of correctly concluding the therapy is worthy of further study was calculated to be 80% if the true underlying response rate was 30%. The probability of incorrectly concluding the therapy is promising was 5% if the true response rate was approximately 10%.21e23 The expected sample size for this study design was a minimum of 15 and a maximum of 28 patients.
Patient Eligibility Patients eligible for this study all had high risk NMIBC with pathologically proven stage T1, Ta or Tis. Patients had high grade disease except 1 who had multifocal recurrent low grade stage Ta disease. All patients were subject to a minimum of 1 prior intravesical BCG induction course. Prior use of intravesical mitomycin C, interferon, gemcitabine, docetaxel or other experimental clinical agents was allowed. If a patient was treated in a prior clinical trial, a minimum of 3 months after completion of the prior protocol was required with documented disease recurrence before enrollment in this study. All patients had grossly visible disease fully resected with pathological confirmation of histology before enrollment. They were offered RC as the gold standard option and refused, or were at unacceptable surgical risk. Patients underwent pretreatment assessment including physical examination, cystoscopy and cross-sectional imaging, as well as complete blood count, basic metabolic panel, hepatic function panel and coagulation profile before study enrollment. Additional inclusion criteria were age 18 years or older, ability to provide informed consent, Eastern Cooperative Oncology Group performance status 0 or 1, mild or no peripheral neuropathy, no hematological disturbances as defined by neutrophil count 1,500/mm3 or less, hemoglobin 9 gm/dl or less, or platelet count 100,000/mm3 or less, no hepatic dysfunction as defined by abnormal bilirubin or liver function tests 2.5 or greater than upper normal limit, no renal dysfunction as defined by serum creatinine 2.0 mg/dl or greater, negative pregnancy test in women of childbearing age and no intravesical therapy within 6 weeks before enrollment. Exclusion criteria were prior systemic taxane therapy, any other malignancy diagnosed within 2 years of study entry (except nonmelanoma skin cancer, chronic lymphocytic leukemia or noninvasive cervical cancer), concurrent treatment with any chemotherapeutic agent, pregnant or lactating women, history of vesicoureteral reflux or an indwelling urinary stent, or administration of any investigational agent within 3 months before study.
Drug Preparation and Administration The dose of nab-paclitaxel was the MDD of 500 mg/100 ml 0.9% NaCl. The dose was instilled intravesically on a
NAB-PACLITAXEL FOR BACILLUS CALMETTE-GUERIN REFRACTORY BLADDER CANCER
weekly basis for 6 weeks as induction and on a monthly basis for 6 months as maintenance in case of response. On the day of each instillation an updated history and physical examination were performed, and a urine pH was measured by dipstick to be in the range of 5 to 7.5 to ensure nab-paclitaxel solubility. Sterile urethral catheterization was performed to empty the bladder and instill nab-paclitaxel solution into the bladder with a drug retention time of 2 hours.
Treatment Assessment and Evaluation After induction treatment, initial response was assessed through urine cytology, cystoscopy with biopsy, directed and random, 6 weeks after the last instillation of the induction nab-paclitaxel course. Cross-sectional imaging was included in the posttreatment evaluation. CR was defined by the absence of any residual carcinoma in the biopsy specimen as well as in cytology following the combination of maximal transurethral resection and nab-paclitaxel. The efficacy of this protocol was measured using the CR rate as the primary end point, and recurrence-free and cystectomy-free survival as the secondary end points. Local toxicity symptoms were monitored throughout treatment, and graded using the Common Terminology Criteria for Adverse Events, version 3.0, published by the National Cancer Institute. Treatment was delayed by 1 week if grade 2 local toxicity developed, then resumed if symptoms improved. Grade 3 or 4 toxicity prompted discontinuation of therapy.
RESULTS A total of 28 patients were enrolled in the study between 2010 and 2013. Median patient age was 76 years (range 33 to 91), and 22 men and 6 women were enrolled. All patients had nonmuscle invasive urothelial carcinoma of the bladder, with disease stage and grade presented in table 1. Only 1 patient had unifocal T1 while all the remaining had multifocal disease. The median number of prior courses of intravesical therapy was 2, with 7 patients who received 1 course and 9 who received 3 or more courses, including enrollment in prior clinical trials of intravesical chemotherapy. Of the 28 patients 6 (21.4%) previously received intravesical
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chemotherapy (mitomycin C or other agents) subsequent to BCG with or without interferon (table 2). Only 1 patient previously responded to BCG then experienced relapse, yet he never received maintenance. No other patient in this study previously received BCG maintenance. Twenty patients refused and 8 were medically unfit for cystectomy. Median followup was 21 months (range 5 to 47). Twenty-six patients completed the 6 intravesical induction instillations and the remaining 2 patients were still included in the analysis of efficacy. On initial posttreatment assessment 6 weeks after the last induction instillation, 10 of the 28 patients (35.7%) had a CR. The pretreatment stages stratified by response status and the posttreatment stages and cytology are presented in table 3. Among the 10 responders 8 received the entire induction course followed by 6 months of maintenance therapy. The 2 who did not complete induction also did not receive maintenance therapy. Of the 10 responders 2 elected to continue on maintenance therapy off protocol following the conclusion of the 6-month maintenance period. One of these patients exhibited positive cytology 14 months after enrollment with normal cystoscopic examination until 45 months of followup, and refused further biopsy. Two patients died of unrelated causes at 11 and 24 months of followup. The remaining 7 patients were disease-free at a median followup of 21 months. All 18 nonresponders were recommended by the urologist to proceed to RC yet only 9 accepted and followed the recommendation. Of these 9 patients 7 are alive with no evidence of local or systemic disease. One died 9 weeks after RC due to perioperative complications with final pathology showing CIS only. A single patient undergoing RC exhibited stage progression to muscle invasive disease (pT2N0M0) on surgical pathology, and eventually died of metastatic urothelial cancer 18 months after treatment initiation. Of the 18 patients who did not respond to nabpaclitaxel therapy 9 did not undergo cystectomy. Table 2. Intravesical treatment history of participants
Table 1. Demographic and clinical characteristics of participants
No. (%) No. (%)
Gender: F M Clinical stage: Ta Ta þ Tis T1 T1 þ Tis Tis only Tumor grade: Low grade/multifocal Ta High grade
6 (21) 22 (79) 4 2 4 5 13
(14) (7) (14) (18) (46)
1 (4) 27 (96)
BCG alone induction BCG alone reinduction BCG maintenance BCG þ interferon Intravesical chemotherapy: Mitomycin Gemcitabine Mitomycinþgemcitabine Valrubicin No. cycles: 1 2 3 4
27 6 0 13 6 1 3 1 1
(96) (21) (46) (21) (3.6) (11) (3.6) (3.6)
7 12 8 1
(25) (43) (29) (3.6)
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NAB-PACLITAXEL FOR BACILLUS CALMETTE-GUERIN REFRACTORY BLADDER CANCER
Table 3. Assessment of patients before and after treatment No. Complete Responders (%)
No. Noncomplete Responders (%)
Before nab-paclitaxel treatment* Stage: Ta Ta þ Tis T1 T1 þ Tis Tis only Stage on biopsy: T0 Ta (þTis) T1 (þTis) Tis Cytology: Malignant Suspicious Benign
3 (30) 0 (0) 2 (20) 1 (10) 4 (40) After nab-paclitaxel treatment
1 2 2 4 9
(5.6) (11) (11) (22) (50)
10 0 (0) 0 (0) 0
0 2 (2) 2 (3) 9
0 (0) 4 (40) 6 (60)
11 (61) 3 (17) 4 (22)
* p<0.001.
Two died of unrelated causes, both within 12 months of initiation of treatment. The remaining 7 patients all had residual high grade NMIBC, 4 have not received further intravesical therapy and 3 went on to receive further intravesical therapy (2 docetaxel and 1 valrubicin), with 1 completely responding to docetaxel and 1 completely responding to valrubicin. None of those 9 exhibited stage progression at a median followup of 21 months. In this study 19 of 28 patients retained their bladders without disease progression or metastasis. RFS was 35.7% at 1 year and 30.6% at 2 years of followup. CFS at 12, 24 and 36 months was 74%, 74% and 55%, respectively. RFS and CFS are presented in Kaplan-Meier survival analysis plots (see figure). Nine patients (32%) experienced adverse events in this study. All events were grade 1 or 2, and included fatigue, urinary urgency and self-limiting hematuria for grade 1 (4 of 28 patients, 14%). Grade 2 toxicities (5 of 28 patients, 18%) included urinary tract infection, frequency and urgency, and gross hematuria. No patient underwent
discontinuation of therapy because of a drug related event. One patient received only 3 of the planned 6 instillations due to unrelated pneumonia, while another patient withdrew from the trial due to recurrent urinary tract infections after receiving only 2 instillations. These infections were multidrug resistant, present for more than 2 years before enrollment and due to incomplete bladder emptying. No grade 3 or higher toxicity was noted.
DISCUSSION High risk NMIBC represents a challenging disease state to manage. While intravesical BCG is a well established first line treatment for patients with NMIBC, patients with recurrence after the initial treatment have lower response rates to subsequent courses.24 BCG was previously compared as an induction agent to adjuvant intravesical chemotherapy. However, it was only compared to mitomycin, epirubicin and doxorubicin.8,25 Alternative agents that have proven successful in the systemic therapy of advanced urothelial carcinoma such as cisplatin, gemcitabine and docetaxel have now been investigated intravesically with varying yet promising results. Intravesical gemcitabine in particular was supported by multiple studies in patients with high risk disease. In a study by Gunelli et al a group of 40 patients without CIS had a CR rate of 95% at 6 months and disease-free survival of 66% at 24 months.26 However, a separate study by Dalbagni et al of 30 patients (which included 23 patients with CIS) showed a 20% disease-free survival at 12 months without the use of maintenance therapy for responders.27 The most recent trial of gemcitabine was conducted by Skinner et al of the Southwest Oncology Group and was reported in 2013.11 They found a 47% complete initial response rate at 3 months and a RFS of 28% and 21% at 1 and 2 years, respectively. Of note, maintenance
Disease-free (A) and cystectomy-free (B) survival after intravesical nab-paclitaxel
NAB-PACLITAXEL FOR BACILLUS CALMETTE-GUERIN REFRACTORY BLADDER CANCER
intravesical gemcitabine was given to complete responders. Intravesical taxane therapy has been a topic of interest at our institution since initiating our initial phase I trial of intravesical docetaxel in 2003. The results of this trial were published in 2006, and demonstrated acceptable safety and efficacy profiles.14 However, no phase II trial of efficacy was conducted.15 Paclitaxel, another taxane, recently became available in an albumin bound formulation, improving its pharmacokinetics and safety profile, and theoretically its efficacy in targeting cancerous cells. In our prospective phase II trial of efficacy in a heavily pretreated high risk population of patients with NMIBC, a CR rate of 35.7% was achieved. More importantly, all patients who responded remained disease-free at 1 year, and RFS at 2 years and at last followup was 30.6%, with a median followup of 21 months. These results demonstrate a durability of response to intravesical nab-paclitaxel induction plus maintenance not seen in any previous taxane based clinical trial. All patients were compliant with the induction and maintenance therapy schedules and specified followup except for 2 patients as described earlier. However, these 2 patients were included in the final analysis of therapy outcomes. Since this was a single arm study in which all complete initial responders were offered monthly maintenance therapy throughout the duration of recurrence-free status for up to 6 additional treatments, the effect of maintenance therapy on durability could not be assessed. With a favorable safety profile, minimal absorption and a 6,000-fold greater bladder tissue concentration for intravesical therapy over systemic therapy,28 maintenance seems to be justified and practical. It is even possible that the durability seen in the current study could be improved with
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additional maintenance treatments beyond those allowed by our protocol. Prospective, randomized studies are required to determine the ideal treatment schedule and the true effect of maintenance intravesical nab-paclitaxel. Although CFS is not a widely studied or a widely accepted outcome in bladder cancer literature, it provides a method to describe the likelihood of bladder preservation in this population facing RC as the standard of care, particularly in studies of similar design and objective. The relatively short followup and limited sample size of this phase II trial limit any broad conclusions regarding the future role of nab-paclitaxel in patients with recurrent high risk NMIBC after BCG. To resolve the role of novel agents in this setting, a definitive randomized phase III trial comparing a novel therapeutic agent with BCG or a similar standard intervention will be required.
CONCLUSIONS This phase II study of intravesical nab-paclitaxel demonstrated significant activity in high risk patients with recurrent NMIBC after treatment with BCG with or without other chemotherapeutic agents. In a heavily pretreated population the limited toxicity profile in conjunction with a CR of 35.7% warrants further investigation. Furthermore, the addition of maintenance therapy resulted in a durability of response not frequently seen in such populations. Either alone or in combination with other agents, nab-paclitaxel is a viable candidate for further study in this high risk population.
ACKNOWLEDGMENTS Jiibril Palmer and Matthew Danzig provided assistance.
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